Recurrent severe behavioural dysregulation in a neurodevelopmental disorder associated with 1q21.1 microdeletion: a case report

Background

Severe behavioural dysregulation with impulsive aggression in neurodevelopmental disorders poses major diagnostic and therapeutic challenges. This is particularly evident in treatment-resistant cases with marked fluctuation and no clear environmental triggers. Increasing evidence from psychiatric genomics highlights the contribution of rare copy number variants, including 1q21.1 microdeletions, in shaping neurodevelopmental trajectories and contributing to complex neuropsychiatric phenotypes. These variants are associated with a broad spectrum of manifestations, including intellectual disability, autism spectrum disorder, and increased risk for psychosis, and are thought to affect neural circuits involved in emotional regulation, salience processing, and cognitive control.

Aims

To describe a treatment-refractory case of recurrent clastic behavioural crises in an adolescent with neurodevelopmental disorder associated with a 1q21.1 microdeletion, and to discuss its neurobiological and clinical implications.

Case Report

We report the case of a 14-year-old male with intellectual developmental disorder and autism spectrum disorder. Since early childhood, he presented persistent difficulties in impulse control, socialisation, and learning. The clinical course was marked by recurrent episodes of severe auto- and hetero-aggressive outbursts across settings, often followed by remorse.

Over a two-year period, he required multiple psychiatric admissions due to escalating risk to others, including prolonged inpatient stays (83 days, 32 days, and >200 days) and a brief home-hospitalisation period. The clinical presentation showed marked fluctuation, with exacerbations characterised by impulsivity, rumination, paranoid ideation, low frustration tolerance, and limited capacity to verbalise distress prior to behavioural escalation.

Multiple pharmacological strategies were trialled, targeting different neurobiological systems including serotonin reuptake inhibitors, dopamine D2 receptor antagonists and partial agonists, alpha-2 adrenergic receptor agonists, mood stabilisers, psychostimulants (including agents modulating voltage-gated ion channels and intracellular signalling pathways), and positive allosteric modulators of GABA-A receptors, without sustained clinical benefit. Suspected iatrogenic effects partially improved following gradual medication optimisation. Non-pharmacological interventions included structured behavioural planning, occupational therapy, psychomotor therapy and the use of mediators for emotional regulation. The therapeutic relationship remained central throughout the intervention/clinical course an

The patient presented with a syndromic phenotype, including non-specific dysmorphic facial features, short stature, dysphagia, chronic constipation, tremor, hypertonia, and gait imbalance. Given the clinical complexity, an extensive aetiological work-up was conducted, including neuroimaging, electroencephalography, laboratory screening, and whole exome sequencing. This was complemented by a multidisciplinary evaluation, involving paediatrics, paediatric neurology, paediatric endocrinology, genetics, and child and adolescent psychiatry.

This led to an whole exome sequencing and the identification of a 1q21.1 (BP3–BP4) microdeletion, providing a unifying explanatory framework for the neurodevelopmental, behavioural, and neurological features, as well as for the fluctuating and treatment-resistant course.

Conclusions

This case illustrates the importance of considering underlying genetic conditions in severe, treatment-refractory behavioural dysregulation in adolescents with neurodevelopmental disorders. It supports emerging evidence from psychiatric genomics linking rare genomic variants to disruptions in neural circuits involved in emotional regulation and impulse control, and underscores the value of multidisciplinary assessment in refining diagnosis, guiding management, and informing prognosis.

References

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